In my previous blog, I discussed how the psychoactive component of marijuana (cannabis), mainly tetrahydrocannabinol (THC), can have a negative impact on your hormones. In this blog, I will delve into the world of cannabidiol (CBD), which has been making quite a buzz lately as a therapeutic panacea.

Although they are derived from the same plant and have quite similar molecular structures, CBD is very different than THC from a clinical perspective, primarily because CBD doesn’t elicit the “high”. Despite its lack of psychoactive effects, CBD has potent anti-inflammatory and anti-seizure properties and an array of other benefits for the body that I will discuss below.

Biochemical Differences Between CBD and THC

CBD is closely related to THC, but with its own unique biochemistry. Although derived from the same plant, CBD is quite different from THC in its actions in the body, mostly the brain. For example, CBD has a lower affinity for the CB1 cannabinoid receptors that bind and are activated by THC. CBD is most closely associated with cannabinoid receptor CB2. CB2 receptors are found primarily in the immune system and blood cells, hence explaining CBD’s ability to help with the inflammatory response [1]. This difference in location between CB1 and CB2 receptors is one of the reasons why CBD doesn’t have the psychotropic effect of THC, or “high”. The other reason is that it acts differently, as an inverse agonist [2]. An agonist is a molecule that activates a receptor, providing the expected effect. An inverse agonist activates the receptor, but creates the inverse, or opposite of the effect expected. This inverse effect allows CBD to counter the effects of THC and other endocannabinoids in the brain and elsewhere in the body.

Another possible mechanism for CBD’s beneficial actions is its indirect effect on the endocannabinoid (cannabinoid-like molecules made naturally within the body) system whereby it blocks anandamide reuptake, which inhibits its enzymatic degradation, allowing it to be retained longer in circulation. Anandamide is the most abundant natural endocannabinoid produced by the body.

First Modern Uses of CBD

CBD really broke onto the scene in 2006 in association with its use in treatment of refractory epilepsy. “Patient zero” is a girl from Colorado named Charlotte who suffers from a rare, lifelong form of epilepsy called Dravet syndrome. Charlotte’s story, propelled to the level of national prominence, featured a wheelchair-bound 5-year-old girl with a feeding tube, whose seizures almost entirely disappeared after her mom gave her CBD extract.

Since then, cannabinoids have been made into multiple FDA-approved drug products. These include Epidiolex, a CBD prescription drug to treat epileptic seizures; Marinol and Cesamet, two synthetic THC medications used to combat the side effects of chemotherapy and wasting disease; and a pain medication using a 1:1 ratio of CBD to THC called Sativex. These drugs are just the tip of the iceberg of what cannabis, and more specifically, CBD, can be used to treat.

Current Medicinal Applications

Pain: One of the most common uses of CBD currently is for treatment of pain. This is generally achieved by the reduction of inflammation. CBD works to reduce inflammation by decreasing adenosine uptake by immune cells, thus down regulating their ability to trigger inflammation through the release of inflammatory cytokines [3]. CBD has also been found experimentally to reduce transcription levels of receptors found in the inflammation pathway in the brain [3].

Bone Loss: CBD may also help reduce bone loss and osteoporosis resulting from loss of estrogens at menopause and with aging. CBD acts on bone by stimulating CB2 expression in osteoblasts and osteoclasts, which can inhibit bone resorption and stimulate bone formation [4,5].

Cancer Treatment: CBD has also been shown to be beneficial in the treatment of certain cancers. These effects are seen through the increase of reactive oxygen species (ROS) in some cancer cell lines [6,7,8]. ROS are extremely reactive and can cause significant damage to healthy tissues and cells within the body if not scavenged almost immediately by antioxidants before they have a chance to do said damage. CBD appears to selectively increase ROS in cancer cells more than normal cells, leading to their death. The mechanism by which this occurs is still unknown. The other important function of CBD in the treatment of cancer is its ability to inhibit breast cancer resistance protein (BCRP) in the cell membranes of cancer cells [9]. BCRP is an efflux pump that is responsible for flushing xenobiotics, compounds not found endogenously in the body, out of cells. Cancer cells, especially those being treated with chemotherapy, upregulate the production of BCRPs, causing the cells to become resistant to chemotherapy, thus rendering the chemotherapy ineffective. By inhibiting BCRP, CBD can therefore enhance the effects of chemotherapeutic agents on cancer cells.

Epilepsy: I wouldn’t be doing CBD justice if I didn’t talk about how it is an effective treatment for some forms of epilepsy [10]. Seizure activity in the hippocampus leads to increased levels of CB1 receptors. In one study blocking CB1 receptors caused an increase in frequency and duration of seizures in rats but did not cause seizures in control rats not prone to seizures [10]. This suggests that CB1 activation is a response to seizures rather than a cause. Studies also show that endocannabinoid levels peak 20 minutes after a seizure, suggesting cannabinoids are important in the protection against seizure activity [10]. The enhancement of the endocannabinoid system by CBD can have beneficial effects in certain types of seizures. 

Effects on the Immune System – Both Good and Bad

The biggest effect CBD has in the body lies within the immune system. Immune cells have the highest concentration of CB2 receptors, allowing CBD to play a role in inflammation as mentioned above. Briefly, the immune system involves two types of immunity, cellular and humoral. Cellular immunity guards against infected cells from bacteria, fungus, and viruses and foreign tissue. This is how the body attacks cancer and rejects transplants. Humoral immunity is the body’s antibody response to infection. Antibodies are produced by B cells. Leukocytes (white blood cells) are also part of the humoral immune system and produce interleukins as a response.

CBD inhibits various immune response factors in both B-cells and T-cells [2,11]. This can have beneficial but also negative effects. For example, the actions of CBD on B-cells can increase a person’s risk of HIV-1 and other infectious disease organisms. This inhibitory effect is cell line specific though, as CBD increases some factors in eosinophils, which play a key role in allergic inflammatory responses [11]. This means that CBD can make the symptoms of some allergic responses worse. In lymphocytes and monocytes, CBD is shown to inhibit the release different inflammatory cytokines, which is the mode of action that allows CBD to have an anti-inflammatory effect [11].

Possibilities for the Future: Mood Disorders and Alzheimer’s

CBD is being looked at as a possible treatment for depression and anxiety through its effects on the CB1 receptors in the brain. Studies show that CBD acts through the modulation of the serotonin 5-HT_1A receptors to work as a fast-acting antidepressant and anxiolytic (anti-anxiety) [12]. A reduced number/affinity of 5-HT_1A receptors has been found in the brains of depressed individuals [13]. This is highly significant because these receptors help facilitate the release of brain-derived neurotrophic factor (BDNF) and are responsible for some of the neuroprotective abilities of the 5-HT receptors [13]. BDNF is present in nearly all brain regions as well as the peripheral nervous system and is important in regulation of developmental processes, neuroprotection, synaptogenesis, and mechanisms of memory and cognition [14]. With low numbers of serotonin receptors in the brain BDNF levels are also likely to be low, thus partially stripping the brain from its nourishing protector. Not surprisingly, low serum BDNF levels are a biomarker for depression [15]. An increase in BDNF is seen with antidepressant behavior modification and is found in response to CBD and the common antidepressant drug, imipramine. High stress situations can also negatively impact BDNF levels. The increase in BDNF after CBD administration is rapid and is not sustained long term [16]. However, long-term, frequent administration of CBD will continue to keep BDNF levels elevated above the baseline [16].

Closely related to serotonin, the sex steroid estrogen also stimulates serotonin as well as BDNF production. Estrogen up-regulates serotonin receptors and enzymes responsible for serotonin synthesis, thereby increasing levels [17]. Fluctuating levels of estrogens that occur with transitions to puberty, throughout menstrual cycles during the fertile years, and then into perimenopause and finally menopause, can play a major role in a woman’s overall feeling of happiness during her life-cycles.  

CBD has also been shown to rapidly increase dendritic spines in the brain which is also indicative of its antidepressant activity [16]. Several studies in rats showed that low doses of CBD had anxiolytic (calming) effects, whereas higher doses did not have the same effect [15]. CBD is being shown as a promising treatment/preventative treatment for Alzheimer’s disease. In Alzheimer’s disease there is an accumulation of β-amyloid plaques. However, it is unknown whether these plaques are the cause or a symptom of Alzheimer’s disease. Decreased levels of BDNF has also been shown in Alzheimer’s patients [18]. CBD has been shown to prevent cell death caused by these β-amyloid plaques and to facilitate hippocampal neurogenesis [19].

Side Effects of CBD

Like most natural products, CBD influences your cytochrome P450 (CYP) family of enzymes responsible for the body’s ability to metabolize both natural endogenous and exogenous molecules to prepare them for excretion. Natural products, foods, and pharmaceutical drugs can up- or down-regulate the activities of the CYP enzymes. Generally, these effects don’t have major impacts on the body. However, when taking pharmaceutical drugs or natural products to treat ailments or diseases, the ability of these enzymes to affect the clearance of these products can be detrimental to your health. A classic example is grapefruit juice. A small glass of grapefruit juice can inhibit some of the CYP enzymes that are important in metabolizing prescription medications. This reduces the clearance of these medications and can lead to an unhealthy accumulation of these drugs. Because of this, it is extremely important to tell your doctor if you are taking CBD so they can adjust the doses of your medications as necessary to ensure they are working as effectively as possible and that no negative side effects occur.

The other side effect of CBD use affects the fetus. As mentioned earlier, CBD inhibits BCRP efflux pumps in cancer cells, but BCRP are also very important in the placenta and are responsible for protecting the fetus from toxins that could be passed from the mother. Endocannabinoids have also shown to have a regulatory role in the placenta by removing damaged cells through apoptosis, and thus CB1 and CB2 receptors are found in the placenta throughout the first 10 weeks of gestation [20]. There is also a high concentration of fatty acid amide hydrolase (FAAH) which is responsible for the metabolism of endocannabinoids and is important in maintaining a very stable concentration in the placenta. When concentrations get too high, cell growth is reduced and cell numbers are too low, which can lead to increased risk of 1^st trimester pregnancy loss [21].

The Need for Further Research

Ongoing research suggests CBD has many therapeutic uses, from epilepsy to providing neuroprotective benefits in the brain. CBD has been less studied than THC so there is a lot of research that has not been done yet. While preliminary work looks promising, as CBD starts gaining more attention and undergoing safety trials regulated by the FDA, the picture of our interactions with CBD will become clearer.

If you are interested in using CBD here are some pointers to help in the process. First, you should always consult with your doctor before trying new treatments, especially if you are on other medications. Second, make sure you are getting your CBD from a trusted source. CBD is not treated as a dietary supplement (yet) and is not regulated as such, meaning there are very few controls in place for the manufacture of CBD products. As such, you want to make sure the manufacturer is doing things the right way. Things to look for are GMP certification, clear labeling of potency and purity, and published quality documents. A lot of quality CBD manufacturers will post their quality documents online showing that the CBD oil extracted from the hemp is free of microbial, heavy metal, pesticide, and residual solvent contamination. Third, make sure to start at a low dosage and slowly increase over time to find the correct dosage for you. Since CBD amounts vary (even from what is on the label, see second point), it is important to find the most appropriate dosage. The amount your friend takes for their symptoms might not be enough for you, or it may be too much. Finally, finding a “full-spectrum” product will be more beneficial as it contains all the other cannabinoids and terpenes found in the plant, not just the isolated compound. I am a firm believer that all compounds in a plant are there working in conjunction with each other and will result in a better treatment than just cherry-picking the compounds that have been studied and determined to be active.

Related Resources

• Blog: The Effects of Cannabis on Your Hormones
• Webinar: New Understandings of the Endocannabinoid System and Women’s Health
• Get Started with ZRT's Serum Testing Today

References

[1] Pagotto U, et al. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocrine Reviews. 2006;27(1):73-100.

[2] Bergamaschi MM, et al. Safety and side effects of cannabidiol, a cannabis sativa Curr Drug Safety. 2011;6(4)237-249.

[3] Burstein S. Cannabidiol (CBD) and its analogs: a review of their effects on inflammation. Bioorganic Med Chem. 2015;23:1377-1385.

[4] Bab I, et al. Cannabinoids and the skeleton: From marijuana to reversal of bone loss. Annals of Med. 2009;41:560-567.

[5] Kogan NM, et al. Cannabidiol, a major non-psychotropic cannabis constituent enhances fracture healing and stimulates lysyl hydroxylase activity in osteoblasts. J Bone Miner Res. 2015;30(10):1905-1913.

[6] Iffland K et al. An update on the safety and side effects of cannabidiol: A review of clinical data and relevant animal studies. Cannabis and cannabidiol research. 2017;2(1):139-154.

[7] McAllister SD, et al. The antitumor activity of plant-derived non-psychoactive cannabinoids. J Neuroimmune Pharmacol. 2015;10(2):255-267.

[8] Singer E, et al. Reactive oxygen species-mediated therapeutic response and resistance in glioblastoma. Cell Death Dis. 2015;6(1):e1601.

[9] Nakanishi T, et al. Breast cancer resistance protein (BCRP/ABCG2): its tole in multidrug resistance and regulation of its gene expression. Chin J Cancer. 2012;31(2):73-99.

[10] Wallace MJ, et al. Cannabinoids: Defending the epileptic brain. J Pharmacol Exp Ther. 2003;307:129-137.

[11] Srivastava MD, et al. Δ⁹ Tetrahydrocannabinol and cannabidiol alter cytokine production by human immune cells. Immunopharmacology. 1998;40:179-185.

[12] Linge R, et al. Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT_1a Neuropharmacology. 2016;103:16-26.

[13] Zanelati TV, et al. Antidepressant-like effects of cannabidiol in mice: Possible involvement of 5-HT_1A Brit J Pharmacology. 2010; 159:122-128.

[14] Kowianski P, et al. BDNF: A key factor with multipotent impact on brain signaling and synaptic plasticity. Cell Mol Neurobiol. 2018;38:579-593.

[15] de Mello Schier AR, et al. Antidepressant-like and anxiolytic-like effects of cannabidiol: A chemical compound of Cannabis sativa. CNS & Neuro Disorder – Drug Targets. 2014;13:953-960.

[16] Sales AJ, et al. Cannabidiol induces rapid and sustained antidepressant-like effects through increased BDNF signaling and synaptogenesis in the prefrontal cortex. Mol Neurobiol. 2019;56(2):1070-1081.

[17] Carbone DL and Handa RJ. Sex and stress hormone influences on the expression and activity of brain-derived neurotrophic factor. Neurosci. 2013;239:295-303.

[18] Budni J, et al. The involvement of BDNF, NGF, and GDNF in aging and Alzheimer’s disease. Aging Dis. 2015;6(5):331-341.

[19] Campos AC, et al. Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol Res. 2016;112:119-127.

[20] Feinshtein V, et al. Cannabidiol enhances xenobiotic permeability through the human placental barrier by direct inhibition of breast cancer resistance protein: an ex vivo study. AM J Obstet Gynecol. 2013;209(6):573.e1-573.e15.

[21] Habayeb OMH, et al. Expression of the endocannabinoid system in human first trimester placenta and its role in trophoblast proliferation. Endocrinology. 2008;149(10):5052-5060.